title: Fatty acid amide hydrolase but not monoacyl glycerol lipase controls cell death induced by the endocannabinoid 2-arachidonoyl glycerol in hepatic cell populations.
abstract: The endogenous cannabinoids anandamide (N-arachidonoylethanolamide, AEA) and 2-arachidonoyl glycerol (2-AG) are upregulated during liver fibrogenesis and selectively induce cell death in hepatic stellate cells (HSCs), the major fibrogenic cells in the liver, but not in hepatocytes. In contrast to HSCs, hepatocytes highly express the AEA-degrading enzyme fatty acid amide hydrolase (FAAH) that protects them from AEA-induced injury. However, the role of the major 2-AG-degrading enzyme monoacylglycerol lipase (MGL) in 2-AG-induced hepatic cell death has not been investigated. In contrast to FAAH, MGL protein expression did not significantly differ in primary mouse hepatocytes and HSCs. Hepatocytes pretreated with selective MGL inhibitors were not sensitized towards 2-AG-mediated death, indicating a minor role for MGL in the cellular resistance against 2-AG. Moreover, while adenoviral MGL overexpression failed to render HSCs resistant towards 2-AG, FAAH overexpression prevented 2-AG-induced death in HSCs. Accordingly, 2-AG caused cell death in hepatocytes pretreated with the FAAH inhibitor URB597, FAAH(-/-) hepatocytes, or hepatocytes depleted of the antioxidant glutathione (GSH). Moreover, 2-AG increased reactive oxygen species production in hepatocytes after FAAH inhibition, indicating that hepatocytes are more resistant to 2-AG treatment due to high GSH levels and FAAH expression. However, 2-AG was not significantly elevated in FAAH(-/-) mouse livers in contrast to AEA. Thus, FAAH exerts important protective actions against 2-AG-induced cellular damage, even though it is not the major 2-AG degradation enzyme in vivo. In conclusion, FAAH-mediated resistance of hepatocytes against endocannabinoid-induced cell death may provide a new physiological concept allowing the specific targeting of HSCs in liver fibrosis.
authors.affiliation: Dept. of Medicine I, University Hospital Bonn, Bonn, Germany. soeren.siegmund@ukb.uni-bonn.de
authors.forename: Sören V
authors.initials: SV
authors.lastname: Siegmund
authors.forename: Alexandra
authors.initials: A
authors.lastname: Wojtalla
authors.forename: Monika
authors.initials: M
authors.lastname: Schlosser
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.forename: Manfred V
authors.initials: MV
authors.lastname: Singer
mesh_terms: D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects; D063388:Endocannabinoids / Q000494:pharmacology*; D005989:Glycerides / Q000494:pharmacology*; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D008994:Monoacylglycerol Lipases; D017382:Reactive Oxygen Species; D000099252:Fatty Acid Amide Hydrolases; C094503:glyceryl 2-arachidonate; C527261:ABHD6 protein, mouse; C527260:Abhd12 protein, mouse
keywords: 2-Arachidonoyl glycerol; Cell death; Endocannabinoids; Fatty acid amide hydrolase; Hepatic stellate cells; Monoacylglycerol lipase